Superb microvascular imaging for distinguishing thyroid nodules: A meta-analysis (PRISMA).

BACKGROUND: Earlier studies have shown that the superb microvascular imaging (SMI) can detect tumor angiogenesis to distinguish thyroid nodules, but there is no systematic review. This meta-analysis aimed to identify the accuracy of ultrasound SMI for the diagnosis of thyroid nodules.
METHODS: We searched PubMed, Cochrane Library, and CBM databases. A meta-analysis was conducted using STATA version 14.0 and Meta-Disc version 1.4 software. We calculated the summary statistics for sensitivity, specificity, positive and negative likelihood ratio (LR+/LR-), diagnostic odds ratio, and the synthetic receiver operating characteristic curve. Data will be pooled by either a fixed-effects model or a random-effects model according to the results of heterogeneity identification.
RESULTS: 11 studies that met the inclusion criteria were included in this meta-analysis. The quality assessment of the study of diagnostic accuracy studies scores of all included studies were ≥22. A total of 1003 thyroid malignant nodules and 957 thyroid benign nodules were assessed. The main outcome included: the pooled sensitivity was 0.81 (95% confidence intervals (CI) = 0.79-0.84), and the pooled specificity was 0.86 (95% CI = 0.84-0.88); the pooled LR+ was 5.79 (95% CI = 4.44-7.54), and the pooled negative LR- was 0.23 (95% CI = 0.20-0.26); the pooled diagnostic odds ratio of SMI in the diagnosis of thyroid nodules was 26.84 (95% CI = 19.13-37.60). The area under the synthetic receiver operating characteristic curve was 0.89 (95% CI = 0.86-0.91). We found no evidence for publication bias (t = 0.72, P = .49).
CONCLUSION: Our meta-analysis indicates that SMI may have high diagnostic accuracy in distinguishing benign and malignant thyroid nodules. SYSTEMATIC REVIEW REGISTRATION: INPLASY202080084.

Introduction

Thyroid cancer is a common malignant disease that accounts for about 1% of all cancer patients.[ Solid thyroid nodules are risk factors for thyroid cancer, and it is important to accurately distinguish thyroid nodules.[ Ultrasonography is the first choice of clinical diagnosis and differentiation of thyroid cancer.[ However, it is difficult to accurately identify the nodule by the atypical ultrasonic wave characteristics because of the complexity and overlapping property of the thyroid nodule ultrasonic image.[

Benign and malignant thyroid nodules display variation in blood flow patterns and vascular morphology that are useful in separating one from the other.[ Color Doppler flow imaging (CDFI) can indicate blood flow in the tumour, but CDFI is not effective in the imaging of some low-velocity microvessels.[ Superb microvascular imaging (SMI) is a new ultrasonic technique that monitors microvascular distribution of tumors quickly, simply and noninvasive, and evaluates microvascular perfusion.[ The SMI uses a multidimensional filter which removes the outgoing signal while saving the slow flow signal. In contrast, conventional Doppler systems use a one-dimensional filter and are insufficient to identify slow flow signals that overlap from background.[ Earlier studies have shown that the SMI can detect tumor angiogenesis to distinguish benign from malignant thyroid nodules.[ However, since all of these studies have limitations on small sample sizes and single centers, there is no clear conclusion. There is no systematic review of SMI for diagnosis of thyroid nodules. The aim of this study is to determine the accuracy of SMI for differential diagnosis of benign and malignant thyroid nodules.

Methods

This meta-analysis protocol has been published.[

Ethics

No ethical approval is required in this study, because it will only analyze published data.

Literature search

PubMed, Cochrane Library and CBM database were searched by two blinded reviewers from January 1st, 2013 to October 1st, 2021. The following keywords and MeSH terms were used: [“thyroid cancer” or “thyroid neoplasm” or “thyroid tumor” or “thyroid nodule”] and [“superb microvascular imaging” or “SMI”]. We also reviewed the bibliography of the searched papers and conducted a manual search to find other potential articles.

Selection criteria

Inclusion criteria included: (1) Study design must have been a clinical cohort study or diagnostic test, (2) the study had to evaluate the accuracy of SMI for differential diagnosis of benign and malignant thyroid nodules, and blood flow grade greater than II was used as the diagnostic criterion of malignancy, (3) all thyroid nodules were histologically confirmed after SMI and (4) data in the study fourfold (2 × 2) tables must have been sufficient for analysis. If the study did not meet these inclusion criteria, it was excluded. When the authors published several studies using the same subjects, the most recent publications or publications with the largest sample size were included.

Data extraction

The relevant data were systematically extracted from all studies by two researchers using standardized forms. The researchers collected the first author's surname, publication year, publication language, research design, sample size, number of lesions, and diagnostic accuracy. The true positives, true negatives, false positives, and false negatives in the fourfold (2 × 2) tables were also collected.

Quality evaluation

Methodological quality was independently assessed by two researchers based on the quality assessment of the study of diagnostic accuracy studies tools (Table 1).

Table 1

Quality evaluation results included in the literature.

First author	1	2	3	4	5	6	7	8	9	10	11	12	13	14
Kong[11]	√	√	√	√	√	√	?	√	√	√	?	√	√	√
Pei[12]	√	√	√	√	√	√	√	√	√	√	?	√	√	?
Zhu[13]	√	√	√	√	√	√	√	√	×	√	?	√	√	√
Zhao[14]	√	√	√	√	√	√	√	?	√	√	?	√	√	√
Li[15]	√	√	√	√	√	√	√	√	×	√	?	√	√	?
Yang[16]	√	√	√	√	√	√	√	?	√	√	?	√	√	×
Chen[17]	√	√	√	√	√	√	√	√	√	√	?	√	√	×
Diao[18]	√	√	√	√	√	√	√	√	×	√	?	√	√	√
Wang[19]	√	√	√	√	√	√	√	?	×	√	?	√	√	×
Li[20]	√	√	√	√	√	√	?	?	√	√	?	√	√	√
He[21]	√	√	√	√	√	√	?	√	×	√	?	√	√	×

√, Yes; ×, No; ?, Vague.

Items related to evaluation contents:

1: Does the case spectrum include various cases and confused disease cases?

2: Does the selection of subjects accurately and clearly define the inclusion and exclusion criteria?

3: Can the gold standard accurately distinguish sick and disease-free States?

4: Is the interval between the gold standard and the test to be evaluated short enough to avoid changes in the condition of the disease?

5: Have all samples or randomly selected samples accepted the gold standard test?

6: Have all cases received the same gold standard test regardless of the results of the trial to be evaluated?

7: Is the gold standard test independent of the test to be evaluated (i.e., the test to be evaluated is not included in the gold standard)?

8: Is the operation of the test to be evaluated clearly described and repeatable?

9: Is the operation of the gold standard test clearly described and repeatable?

10: Are the results of the test to be evaluated interpreted without knowing the results of the gold standard test?

11: Is the interpretation of the results of the gold standard test carried out without knowing the test results to be evaluated?

12: Are the clinical data available when interpreting the test results consistent with the clinical data available in practical application?

13: Are hard to interpret/intermediate test results reported?

14: Are the cases withdrawn from the study explained?

Statistical analysis

STATA version 14.0 (Stata Corp, College Station, TX) and Meta-Disc version 1.4 (Universidad Complutense, Madrid, Spain) software were used for meta-analysis. The sensitivity effect, singularity, positive and negative likelihood ratio ((LR+/LR−) are calculated, and the threshold effect is evaluated using the 95% confidence interval (CI). The summary receiver operating characteristic (SROC) curve and corresponding area under the curve were determined. The threshold effect was assessed using Spearman correlation coefficients. The Cochran's Q-statistic and I2 test were used to evaluate potential heterogeneity between studies. If significant heterogeneity was detected (Q test P < .05 or I2 test >50%), then a random effects model or fixed effects model was used. A sensitivity (Sen) analysis was performed to evaluate the influence of single studies on the overall estimate. We used Begger's funnel plots and Egger's linear regression tests to investigate publication bias.

Results

Features of inclusion studies

The keywords search identified 65 articles. Review of the titles and abstracts of all articles resulted in exclusion of 42 articles. Review of full texts and data integrity lead to exclusion of 11 other studies, leaving evaluation of 11 studies.[Figure 1 shows the selection process of eligible studies. 11 studies analyzed included 1003 thyroid malignant nodules and 957 thyroid benign nodules. The study characteristics and methodological quality are summarized in Table 2. The quality assessment of the study of diagnostic accuracy studies scores of all included studies were ≥22.

Figure 1

Flow chart of literature search and study selection. 11 studies were included in this meta-analysis.

Table 2

Baseline characteristics and methodological quality of all included studies.

							SMI 2 × 2 table				QUADAS score
First author	Year	Country	Language	Sample size	Age (y)	Instrument	TP	FP	FN	TN
Kong[11]	2017	China	English	113	42 (20–75)	Toshiba Ap1io400	60	3	19	31	24
Pei[12]	2015	China	English	196	–	Toshiba Ap1io500	92	5	26	73	24
Zhu[13]	2018	China	English	76	49.6 ± 13.2	Toshiba Ap1io500	25	7	4	40	24
Zhao[14]	2019	China	Chinese	296	–	Toshiba Ap1io500	105	21	34	136	23
Li[15]	2017	China	Chinese	254	39.0 ± 16.5	Toshiba Ap1io500	58	23	15	158	22
Yang[16]	2017	China	Chinese	236	49.4 ± 12.5	Toshiba Ap1io500	33	12	7	48	21
Chen[17]	2017	China	Chinese	163	45.2 ± 18.5	Toshiba Ap1io500	48	6	10	99	22
Diao[18]	2016	China	Chinese	68	44.8 ± 17.6	Toshiba Ap1io500	24	2	3	39	23
Wang[19]	2021	China	Chinese	525	46.6 ± 18.6	Toshiba Ap1io500	306	37	48	134	22
Li[20]	2020	China	Chinese	100	19–68	Toshiba Ap1io500	36	11	9	44	21
He[21]	2020	China	Chinese	69	43.9 ± 10.2	Toshiba Ap1io500	30	6	11	22	23

FN = false negatives, FP = false positives, TN = true negatives, TP = true positives.

Quantitative data synthesis

Random effect models were used because there was apparent heterogeneity during the study. The Sen analysis was carried out without any apparent interference with the result of the meta-analysis (Fig. 2). The pooled Sen was 0.81 (95% CI = 0.79–0.84); the pooled specificity (Spe) was 0.86 (95% CI = 0.84–0.88)(Fig. 3); the pooled LR+ was 5.79 (95% CI = 4.44–7.54); and the pooled negative LR− was 0.23 (95% CI = 0.20–0.26) (Fig. 3). There was no significant correlation (r = 0.132, P = 0.699) between Sen and Spe. The pooled diagnostic odds ratio of SMI in the diagnosis of thyroid nodules was 26.84 (95% CI = 19.13–37.60) (Fig. 4). The area under the SROC curve was 0.89 (95% CI = 0.86–0.91) (Fig. 5). There was no evidence of asymmetry in the funnel plot (Fig. 6). Egger's test showed no strong statistical evidence for the release bias (t = 0.72, P = .49).

Figure 2

Sensitivity analysis. No study had an obvious interference with the results. CI = confidence intervals, OR = odds ratio.

Figure 3

Forest plots for the accuracy of SMI for the diagnosis of thyroid nodules: (A) Sensitivity. (B) Specificity. (C) Positive likelihood ratio. (D) Negative likelihood ratio. SMI = superb microvascular imaging.

Figure 4

Forest plot of DOR of SMI for the diagnosis of thyroid nodules. DOR = diagnostic odds ratio, SMI = superb microvascular imaging.

Figure 5

SROC curve for the accuracy of SMI in the diagnosis of thyroid nodules. AUC = area under curve, SMI = superb microvascular imaging, SROC = summary receiver operator characteristic.

Figure 6

Begger's funnel plot of publication bias on the pooled OR. No publication bias was detected in this meta-analysis. OR = odds ratio.

Ethics and dissemination

We will not obtain ethic documents because this study will be conducted based on the data of published literature. We expect to publish this study on a peer-reviewed journal.

Discussion

Thyroid nodules are common findings, and accurate differentiation is important for clinical decision making. High resolution ultrasound plays an important role in differential diagnosis.[ The ultrasonic features of thyroid malignant nodules were low echo, obscure, minute calcification, and aspect ratio >1. These findings increase the possibility that the node is malignant. However, no single ultrasound feature can independently diagnose malignant nodules.[ The blood flow distribution patterns of benign and malignant thyroid nodules are different.[ Blood vessel and blood flow characteristics of thyroid nodules were used for differential diagnosis of benign and malignant thyroid nodules.[ However, the value of the color Doppler flow pattern in the diagnosis of benign and malignant thyroid nodules is controversial.

SMI uses high resolution Doppler Technology (Aplio diagnostic equipment) to construct a high-density beamforming machine. Conventional Doppler ultrasound reduces the speed of slow blood flow using filtering to eliminate noise artifacts and motion artifacts. SMI technology can specify the blood flow generated by blood flow and tissue motion, and can display the actual blood flow data using the adaptive blood flow calculation method.

The study demonstrated that SMI accurately segregated benign from malignant lesions. This is secondary to the fact that the SMI has the advantage of identifying low velocity blood flow without being affected by the CDFI related motion artifacts. The SMI was an aid to Gray scale us and showed improvement in diagnostic performance in the differentiation of benign and malignant thyroid nodules alone or by either CDFI.[ SMI is expected to complement more than replace US. In theory, current meta-analysis emphasized that SMI is used in lesions like thyroid disease and other types of breast lesions.

The technical performance and accuracy of SMI for differential diagnosis of benign and malignant thyroid nodules were systematically evaluated. The pooled Sen, Spe, and the area under the SROC curve of SMI in the diagnosis of thyroid nodules were 0.79, 0.89, and 0.89, respectively. The values of CDFI and contrast-enhanced ultrasound are 0.65, 0.78, 0.77 and 0.82, 0.89, 0.85.[ A study about SMI in the diagnosis of breast cancer, the pooled Sen, Spe, and diagnostic odds ratio of were 0.81, 0.71, and 46.97.[ These results coincide with the potentially high diagnostic accuracy of SMI for different tumors, suggesting that SMI is a good means for differential diagnosis of benign and malignant thyroid nodules, and predicts the prognosis of patients with thyroid nodules. There was no significant relationship between Sen and SPE in this study. The results did not find direct evidence of the publishing bias. These data suggest that the SMI is an accurate and non-invasive tool for qualitative diagnosis of thyroid nodules consistent with previous studies.

Although it is the first meta-analysis focusing on the diagnostic accuracy of SMI for thyroid nodules, our research is still limited. First, the evaluated study had a relatively small sample size. There was not enough data to evaluate the accuracy of SMI. In addition, the retrospective nature of the meta-analysis leads to the subject selection bias. In addition, most studies started with a single geographical area (i.e., China). Such positional limitations may adversely affect the reliability and validity of the results.

In conclusion, the present meta-analysis suggests that SMI has high diagnostic accuracy in identifying benign and malignant thyroid nodules. These results suggest that SMI is considered in the diagnosis thyroid nodules.

Acknowledgments

We would like to acknowledge the helpful comments on this paper received from our reviewers.

Author contributions

Conceptualization: Changfu Zhu, Cong Wang, Xin Jin.

Data curation: Cong Wang, Congliang Tian.

Investigation: Cong Wang, Congliang Tian.

Project administration: Hui Jin, Ye Tao.

Software: Changfu Zhu, Cong Wang, Xin Jin.

Visualization: Cong Wang, Congliang Tian.

Writing – original draft: Hui Jin, Ye Tao.

Writing – review & editing: Changfu Zhu, Cong Wang, Xin Jin.